Flow-mediated dilation (FMD) is the standard tool used to assess endothelial function. The premise behind the standard FMD test is that it serves as an endothelial-dependant nitric oxide bioassay; however, the endothelium may release additional dilatory molecules which contribute to FMD, most notably prostacyclin and endothelial-derived hyperpolarizing factor. The relative importance of these molecules to the dilatory response may vary substantially among individuals, particularly in response to a number of diseased states. This review discusses how each of these molecules may contribute to vasodilation, and considers the circumstances in which they may vary.
Hydrogen peroxide-inducible clone-5 (Hic-5) is a focal adhesion scaffold protein primarily expressed in vascular and visceral smooth muscle cells. We recently generated mice lacking Hic-5, which grew with no apparent abnormality (Kim-Kaneyama J, et al. J Mol Cell Cardiol. 2011;50(1):77-86). However, we discovered that recovery of arterial media following vascular injury is delayed significantly in Hic-5 knockout mice consequent to enhanced apoptosis of cultured vascular smooth muscle cells after mechanical stress; thus, Hic-5 is regarded as a novel factor in vascular remodeling. The Hic-5 gene is also induced by transforming growth factor-β, a well-known accelerator in fibrosis. Hic-5 involvement in various fibrotic disorders, e.g., scar formation, keloid formation and glomerulosclerosis, has been proposed. siRNA silencing of Hic-5 in a breast cancer cell line reduces its invasiveness; moreover, Hic-5 serves as a steroid hormone co-activator and likely participates in endometriosis and prostate cancer. Thus, functional characterization of Hic-5 in various pathophysiological conditions may afford novel mechanistic insights into a wide variety of diseases.
Aim: Lipid-lowering medications have been suggested to have a potential benefit in the treatment of chronic kidney disease (CKD) such as diabetic nephropathy. Although ezetimibe has been widely used to lower serum cholesterol levels, the effect of this drug on diabetic nephropathy remains unclear. In the present study, therefore, we examined the protective effect of ezetimibe on diabetic nephropathy in db/db mice. Method: Db/db mice were fed a standard diet with 0.01% (w/w) of ezetimibe for 8 weeks from 8 weeks of age. Results: Treatment with ezetimibe did not affect food intake, body weight gain, adiposity, or blood pressure in db/db mice. Ezetimibe also had no effect on glucose metabolism such as fasting plasma glucose and insulin; however, it markedly reduced plasma lipid levels and hepatic lipid contents and reduced the urinary excretion of albumin by 50% in db/db mice, suggesting the effect of ezetimibe on diabetic nephropathy. Furthermore, ezetimibe improved glomerular hypertrophy. Although ezetimibe had no effect on oxidative stress measured by urinary 8-OHdG in db/db mice, the plasma adiponectin level was normalized, and the expression of adiponectin receptor 1 in the kidney was increased by ezetimibe treatment. Conclusion: Our data suggest that ezetimibe can improve early diabetic nephropathy through its hypolipidemic effect, and the amelioration of adiponectin resistance may also be responsible for the renoprotective effect of ezetimibe as its underlying mechanism.
Aim: Serum albumin and globulin have important roles in atherosclerosis development; however, separate studies exploring the relationship between albumin or globulin and coronary heart disease (CHD) have been conducted. We explored whether there was a synergistic effect of albumin and globulin on the presence of CHD. Methods: A total of 395 patients aged 50-74 years with angiographically documented CHD were recruited, and 596 age- and sex-matched controls without CHD were randomly selected from the general population. The association of albumin and globulin with CHD was analyzed using conditional logistic regression after adjusting for traditional CHD risk factors. Results: Mean values of serum albumin and globulin were significantly lower in cases than in controls (p<0.001). In the fully adjusted model, compared with participants whose albumin (≥47.3 g/L) and globulin (≥25.6 g/L) levels were both higher than the median levels in these participants, the odds ratio for CHD was 1.59 (p= 0.048) for participants with higher albumin (≥47.3 g/L) but lower globulin (<25.6 g/L), 2.79 (p<0.001) for participants with lower albumin (<47.3 g/L) but higher globulin (≥25.6 g/L), and 16.03 (p<0.001) for participants with lower levels of both albumin (<47.3 g/L) and globulin (<25.6 g/L). Conclusions: Low serum albumin and globulin are independently associated with CHD. The synergistic association of both low albumin and low globulin with CHD is greater than either one alone. The synergistic effect deserves further investigation.
Aim: FTO is the most important polygene for obesity and type 2 diabetes. Our aims were to investigate whether a variant in FTO affects glucose dysregulation through its effect on fat accumulation or distribution, and when and how FTO influences fat accumulation and distribution and glucose dysregulation from birth until midlife. Methods: A total of 454 Japanese female university students (mean age: 20 years) and 132 middle-aged women (mean age: 50 years) who were the biological mothers of the students underwent the following: genotyping for rs1558902 in the FTO gene, assessment of fat accumulation and distribution, obesity-related metabolic traits and serum adipokine measurement. A subsample of 364 students reported their weight history since birth. Results: The A allele in rs1558902 was substantially less common in young and middle-aged Japanese women (18 and 17%, respectively) than in the European population (45%). The strong effect of genotype AA on BMI was evident at age 12, 15, 20 and 50 years whereas there was no effect on birth weight. In young and middle-aged women, the variant was strongly associated with higher body weight and fat mass. The effects on abdominal girth, fasting glucose, homeostasis model assessment insulin resistance and HbA1c were evident in mothers but not in students. In addition, genotype AA was associated with increased white blood cell counts and hsCRP in mothers only. Associations with fasting glucose, insulin resistance, and white blood cell counts remained after correction for BMI, abdominal girth and fat mass. In multiple logistic regression analysis, AA homozygote in FTO was associated with higher odds of overweight (BMI ≥25kg/m2) in young (OR 1.73 (95%CI 1.06-30.0)) and middle-aged women (OR 1.73 (95%CI 1.06-30.0)). It was also associated with higher odds of abdominal fat accumulation (abdominal girth ≥90cm, OR 1.73 (95%CI 1.06-30.0)) and fasting hyperglycemia (≥100mg/dL) (OR 1.87(95%CI 1.05-40.4)) in middle-aged mothers. Conclusion: Despite the small sample size, the low average BMI, and the low risk allele frequency, a genetic variation at the FTO locus was related to greater weight gain before age 12 in Japanese women. At age 20, it was related to general adiposity. In midlife, however, it was related to abdominal adiposity in addition to general adiposity, fasting hyperglycemia, higher HbA1c and subtle systemic inflammation. Fasting hyperglycemia associated with higher HbA1c in midlife was independent of its effects on general and abdominal adiposity.
Aim: High density lipoprotein (HDL) has multi-antiatherogenic effects such as antioxidation and anti-inflammation, in addition to being a key mediator of reverse cholesterol transport. Probucol, known as a lipid lowering drug, is also a potent antioxidant, but it decreases serum HDL cholesterol (HDL-C) levels. To elucidate the effect of probucol on antioxidant properties of HDL, we investigated the function of HDL derived from patients with heterozygous familial hypercholesterolemia (FH) who have been treated with probucol. Methods and Results: Probucol-treated FH patients (n=21) showed a 47% reduction of serum HDL-C levels compared to probucol-untreated FH patients (n=15). High performance liquid chromatography (HPLC) analysis revealed that probucol diminished HDL particle size compared to the non-treated group. Antioxidant capacity of HDL was evaluated by its effect to protect reference LDL from oxidation induced in the presence of an oxidizing agent, AAPH. The HDL derived from the probucol-treated group demonstrated a significantly prolonged time to start oxidation by 112%, decreased the maximum oxidation rate by 14%, and lowered the maximum concentration of conjugated dienes formation by 15%. Furthermore, HDL-associated paraoxonase 1 (PON1) activity, but not platelet-activating factor acetyl-hydrolase (PAF-AH) correlated with these measurements of HDL anti-oxidative activity. Treatment with probucol in vitro and inhibition of PON1 activity demonstrated that probucol in HDL particles and increase of PON1 activity might largely contribute to the increase of HDL anti-oxidative activity. Conclusion: Probucol reduced HDL-C levels and HDL particle size in patients with heterozygous FH, while it concomitantly enhanced HDL anti-oxidative properties, possibly through increasing PON1 activity.
Aim: Multiple risk factor syndrome is a target for the prevention of coronary artery disease (CAD). A cluster of multiple risk factors, such as hypertension, glucose intolerance, and/or dyslipidemia, is encountered in Japanese without and with excess visceral fat. The present study investigated the relationship between multiple risk factor accumulation and CAD in Japanese without and with visceral fat accumulation. Methods: The study subjects comprised 257 Japanese with suspected CAD (males/females= 153/ 104), who underwent 64-row multislice computed tomography (CT) coronary angiography and visceral fat area (VFA) measurement by CT. Based on the Japanese criteria for visceral fat accumulation, they were divided into those with VFA <100 and≥10cm2. Results: In subjects with VFA <100 cm2, the age- and sex-adjusted odds ratios (ORs) for 2 and 3 risk factors were 5.33 (95% confidence intervals; 1.04-27.38, p=0.0449) and 4.07 (0.72-23.15, p=0.1138), respectively, compared with VFA <100 cm2 and 0 risk factor set at 1.0 (p=0.0569 for trend). In contrast, the respective ORs for subjects with VFA ≥100 cm2 were much higher [6.46 (1.25-33.44, p=0.0261) and 20.42 (3.60-115.73, p=0.0007)] (p<0.0001 for trend). The multivariate adjusted model demonstrated a significant relative excess CAD risk of 1.08 (p=0.0484) and 5.01 (p<0.0001) for the interactions of 2 risk factors and VFA ≥100cm2, and 3 risk factors and VFA ≥100 cm2, whereas multiple risk factor accumulation was not related with the increase of CAD risk in subjects with VFA <100cm2. Conclusions: Coexistence of visceral fat and risk factor accumulations is strongly associated with CAD in Japanese.
Aim: Cigarette smoking is a strong risk factor for atherosclerotic disease; however, it remains unclear whether the impact of other risk factors differs by smoking status. The aim of this study was to investigate this issue, especially with regard to low-density and high-density lipoprotein (LDL/HDL) levels. Methods: In total, 448 healthy, middle-aged men (aged 37 to 61) participated in this study. Smoking habits were recorded, carotid intima-media thickness (IMT) was measured by B-mode ultrasound, and serum lipids and other biochemical parameters were determined from fasted blood samples. Results: Among the overall subjects, multivariate regression analyses showed that IMT was significantly associated with age (p < 0.0001 for mean IMT, p= 0.002 for max IMT), body mass index (BMI, mean IMT, p= 0.028), LDL-C levels (mean/max IMT, p= 0.001), HDL-C levels (max IMT, p= 0.022) and current smoking habit (mean IMT, p=0.012). Subgroup analyses according to smoking status revealed that LDL-C levels were significantly associated with mean/max IMT in current smokers (p=0.001) but not in ex- or nonsmokers (never smoked subjects). After adjusting for age, BMI, systolic blood pressure, hemoglobin A1c and serum lipids, mean IMT respectively increased and decreased progressively across LDL-C and HDL-C quartiles (p= 0.004 and 0.045) in the overall subjects. These associations were observed in current smokers (p= 0.01) but not in ex- or nonsmokers for LDL-C, and were observed in ex- and nonsmokers (p= 0.025, 0.017, respectively) but not in current smokers for HDL-C. Conclusion: The impact of LDL-C/HDL-C levels on carotid IMT differs by smoking status. These observations imply that distinct mechanisms are involved in the (anti) atherogenesis of LDL/HDL according to smoking status.
Aim: The Japan EPA Lipid Intervention Study (JELIS) reported a 19% reduction of the risk for coronary artery disease after long-term use of pure eicosapentaenoic acid (EPA) in Japanese patients with hypercholesterolemia. The variation in plasma fatty acid composition influenced the risk of coronary events. The aim of this study was to examine in JELIS participants the possible correlation of changes in plasma fatty acids with those of serum lipids. Methods: The coefficient for the correlation between the absolute change in plasma fatty acid concentrations and the changes in serum lipids was calculated in 13,901 JELIS participants. Results: Low-density lipoprotein (LDL) cholesterol exhibited a positive correlation with docosahexaenoic acid (DHA; r=0.117 in control group, r=0.155 in EPA group) and linoleic acid (r=0.139 in control group, r=0.177 in EPA group), but the correlation coefficients with EPA (r=0.097 in control group, r=−0.032 in EPA group) were less than 0.1. We distributed the patients into 9 groups according to tertiles of the change in EPA and DHA. The average absolute decrease of LDL cholesterol and L/H ratio in each group was significantly smaller (p<0.001) in the DHA-high tertile, but not in any EPA tertile. Conclusion: The changes in DHA, but not in EPA, showed a positive correlation with the changes in LDL-cholesterol.
Aim: Intima-media thickness (IMT) is considered a surrogate measurement of atherosclerosis but this is still under debate. Methods: To evaluate the relationship between carotid IMT and atherosclerosis, postmortem specimens of the distal segments of the left common carotid artery (CCA) from 133 Korean men aged from 20 to 78 years were used for histopathology and computer-assisted morphometry. Blood lipids and atherosclerosis-associated collagen and elastin were quantitatively analyzed. Results: Correlation coefficients of IMT were smaller than those of intima thickness but IMT was well associated with age (r= 0.55,p <0.00001), atherosclerosis score (or grade, AS, r= 0.73,p < 0.00001), plaque area (PA, r= 0.72,p <0.00001), total cholesterol (TC, r= 0.69,p <0.00001), low-density lipoprotein cholesterol (LDL-c, r= 0.72,p <0.00001) and triglyceride (TG, r= 0.38,p < 0.001). Coronary artery stenosis (CAS) and coronary calcification were also well associated with age (p <0.00001), IMT (p <0.005) and PA (p <0.00001). When IMT was thicker than 1 mm, the possibility of carotid atherosclerosis accompanied with CAS and coronary calcification, TC, LDL-c and TG was much higher (CAS with coronary calcification,p <0.005; TC,p <0.00001; LDL-c,p < 0.00005; TG,p <0.00001). Collagen tended to increase while elastin tended to decrease as AS increased (p <0.005); collagen increased and elastin decreased (p <0.00001) when comparing plaque to the plaque-free area in the same segment. Conclusion: These results support that the carotid IMT in association with TC, LDL-c and TG can be used as a good surrogate marker of atherosclerosis and predictor of coronary heart disease. Plaque formation may influence significant quantitative changes in collagen and elastin.